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Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15–25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.

The gene is implicated in neurodevelopmental and psychiatric disorders, with patient mutations leading to intellectual disability, microcephaly, and autistic behavior. While AUTS2's chromatin-and RNA-related functions are recognized, its direct binding to RNA in human neural progenitors has not been previously demonstrated. Here, we used ChIP-seq and eCLIP-seq in human neural progenitor cells (NPCs) to map AUTS2's chromatin targets and, for the first time, its direct RNA interactome. AUTS2 knockdown in NPCs led to widespread gene expression changes and impaired cell proliferation, migration, and neurite outgrowth. Integrated analysis revealed downregulation of Wnt pathway genes, notably , among targets directly bound by AUTS2 at both chromatin and RNA levels. Supplementation with WNT7A rescued cellular phenotypes in AUTS2-deficient NPCs, underscoring the significance of Wnt signaling. These findings highlight AUTS2's central role in human neurodevelopment and provide mechanistic insight into how its disruption may contribute to the pathology of neurodevelopmental disorders.

The phenomenon of dropout in higher education needs the acknowledging of its multi-domain complexity. In the post-pandemic era, exhaustion may be a relevant feature affecting students. This cross-sectional study aimed primarily to test a predictive model of five domains of variables (background, academic, social, psychological, and economic) on dropout intention, in a relation mediated by academic exhaustion. Secondarily, it aimed to assess the structural invariance of this model across working status (working vs. non-working students) and residence status (living away from family's residence vs. living in family residence). If these groups are differently affected by dropout determinants, specific dropout prevention measures should be implemented. A stratified sample of 1402 Portuguese university students aged between 19 and 45 years (M = 22.87, SD = 3.64), selected through a convenience quota method, was assessed for background, academic, social, psychological, and economic variables using self-report instruments. Structural equation modelling was used. The predictive model explained 51% of the variance in dropout intention. Academic exhaustion was the stronger predictor (β = 0.523, p < .001), followed by social connecteness to the campus (β = -31, p < .001), vocational difficulties (β = 0.274, p < .001), and course value (β = -0.256, p < .001). Except for the course value, and family educational level, all significant predictors had their effect on dropout intention through academic exhaustion. The model was invariant across working and residence status. This study shows the relevance of students' academic exhaustion experiences as a pathway through which different types of factors exert their influence on students´ dropout intentions. The invariance of the predictive model of dropout intention across different groups points the robustness of the model and the relevance of the integrated variables. The results emphasize the importance of student´s individual factors (e.g., academic exhaustion, lack of fit with the course) in dropout decisions, also stressing the role of academic institutions and of the education system in addressing this phenomenon, concerning academic workload, vocational orientation, social environment, and financing.

Objectives Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late‐life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. Methods/design We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM‐V criteria), aged 60–90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. Results TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale‐21, r = −0.325, p = .004) and medical burden (r = −0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). Conclusions We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression. Our study explores and examines the relationship between telomere length (TL) and Late‐Life Depression (LLD), considering the severity of depressive episodes. We found that TL was significantly shorter in the LLD than control participants and was negatively correlated with the severity of depressive symptoms and medical burden. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression.

Psychiatric disorders are among the leading causes of disease burden worldwide. Despite their significant impact, their diagnosis remains challenging due to symptom heterogeneity, psychiatric comorbidity, and the lack of objective diagnostic tests and well-defined biomarkers. Leveraging genomic, epigenomic, and fragmentomic technologies, circulating cell-free DNA (ccfDNA)–based liquid biopsies have emerged as a potential non-invasive diagnosis and disease-monitoring tool. ccfDNA is a DNA species released into circulation from all types of cells through passive and active mechanisms and can serve as a biomarker for various diseases, namely, cancer. Despite their potential, the application of ccfDNA in neuropsychiatry remains underdeveloped. In this review, we provide an overview of liquid biopsies and their components, with a particular focus on ccfDNA. With a summary of pre-analytical practices and current ccfDNA technologies, we highlight the current state of research regarding the use of ccfDNA as a biomarker for neuropsychiatric disorders. Finally, we discuss future steps to unlock ccfDNA’s potential in clinical practice.

Background: The cell cycle is a critical mechanism for proper cellular growth, development and viability. The p16INK4a and p21Waf1/Cip1are important regulators of the cell cycle progression in response to internal and external stimuli (e.g. stress). Accumulating evidence indicates that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces, among others, molecular and morphological alterations, reflecting behavioral changes. Here, we investigated if the p16INK4a and p21Waf1/Cip1 expression are associated with behavioral outcomes. Methods: PFC mRNA and protein levels of p16INK4A and p21Waf1/Cip1 of mice (6 independent groups of C57BL/6J, 8 mice/group, 50% female) exposed from 0 to 35 days of chronic restraint stress (CRS) were quantified by qPCR and Western Blot, respectively. Correlation analyses were used to investigate the associations between CKIs expression and anxiety- and depression-like behaviors. Results: Our results showed that the prefrontal cortex activated the cell cycle regulation pathways mediated by both CKIs p16INK4A and p21Waf1/Cip1 in mice exposed to CRS, with overall decreased mRNA expression and increased protein expression. Moreover, correlation analysis revealed that mRNA and protein levels are statistically significant correlated with anxiety and depressive-like behavior showing a greater effect in males than females. Conclusions: Our present study extends the existing literature providing evidence that prefrontal cortex cells respond to chronic stress exposure by overexpressing CKIs. Furthermore, our findings indicated that abnormal expression of p16INK4A and p21Waf1/Cip1 may significantly contribute to non-adaptive behavioral responses.

Exosomes from brain cells, such as neuron-derived (NDEs) and astrocyte-derived exosomes (ADEs), can cross the blood-brain barrier and be detected in peripheral circulation. These vesicles facilitate communication between the central nervous system (CNS), neuroendocrine, and immune systems, carrying miRNAs and proteins that are protected from degradation. While exosomes are well-studied in Alzheimer's Disease (AD), their role in Mild Cognitive Impairment (MCI) and Late-Life Depression (LLD)-which may be prodromal stages of dementia-remains unclear. This project aims to identify biosignatures in NDEs, ADEs, and plasma to explore molecular profiles shared by LLD, MCI, and AD. We recruited 40 LLD subjects, 25 with MCI, 24 with AD, and 31 age- and gender-matched healthy controls. After psychiatric evaluation, blood samples were collected, centrifuged to obtain platelet-free plasma, and stored at -80°C. Total exosomes were isolated using size exclusion chromatography and analyzed via NanoSight Pro nanotracking. NDEs and ADEs were quantified using the vFC™ vesicle flow cytometry kit on a CytoFlex system, while protein cargo was analyzed with Quanterix, SMCpro, and LX200. Five neuropsychiatric-associated miRNAs were assessed: miR-100-5p, miR-l-3p, miR-184, miR-221-3p, miR-766, and miR-5680. LLD and MCI showed no differences in NDEs and ADEs compared to controls, while AD had elevated levels. No microRNA differences were found between LLD and controls, but five of six miRNAs were reduced in AD. Proteomic analysis revealed persistent neuroinflammation in AD compared to LLD and MCI. These findings suggest compromised brain-periphery communication in MCI, LLD, and AD, highlighting exosomes as a window into the molecular pathology of these disorders.

Introduction The biological mechanisms linking mild cognitive impairment (MCI) and major depressive disorder are not well understood. We investigated whether molecular senescence changes in older adults are associated with a history of major depressive disorder (MDD) or MCI. Methods We included 371 participants: 167 with MCI; 62 cognitively normal with a history of MDD; 97 with MDD+MCI; and 45 cognitively unimpaired (CU) without a history of MDD. The candidate Senescence‐Associated Secretory Phenotype (SASP) biomarkers were measured in the plasma using a customized LUMINEX assay. Results The MDD+MCI group had a higher SASP index than the other groups (P < .001). A higher SASP index was significantly associated with worse global cognitive performance, executive dysfunction, slower processing speed, and episodic memory deficits. Discussion Our study suggests that increased molecular changes are associated with cognitive impairment in older adults with MDD and indicate that accelerated biological aging is an underlying feature of MDD.

Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population. To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults. A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021. Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks. The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples. There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P = .006). In contrast, no individual SASP factors were associated with remission in LLD. Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD. ClinicalTrials.gov Identifier: NCT00892047.

Ocular infection with Toxoplasma gondii causes toxoplasmosis in mice. However, following ocular infection with tachyzoites, the cause of the accompanying progressive changes in hippocampal-dependent tasks, and their relationship with the morphology and number of microglia, is less well understood. Here, in 6-month-old, female BALB/c mice, 5 μl of a suspension containing 48.5 × 10 6 tachyzoites/ml was introduced into the conjunctival sac; control received an equal volume of saline. Before and after instillation, all mice were subject to an olfactory discrimination (OD) test, using predator (cat) feces, and to an open-field (OF) task. After the behavioral tests, the animals were culled at either 22 or 44 days post-instillation (dpi), and the brains and retinas were dissected and processed for immunohistochemistry. The total number of Iba-1-immunolabeled microglia in the molecular layer of the dentate gyrus was estimated, and three-dimensional reconstructions of the cells were evaluated. Immobility was increased in the infected group at 12, 22, and 43 dpi, but the greatest immobility was observed at 22 dpi and was associated with reduced line crossing in the OF and distance traveled. In the OD test, infected animals spent more time in the compartment with feline fecal material at 14 and at 43 dpi. No OD changes were observed in the control group. The number of microglia was increased at 22 dpi but returned to control levels by 44 dpi. These changes were associated with the differentiation of T. gondii tachyzoites into bradyzoite-enclosed cysts within the brain and retina. Thus, infection of mice with T. gondii alters exploratory behavior, gives rise to a loss in predator’s odor avoidance from 2 weeks after infection, increased microglia number, and altered their morphology in the molecular layer of the dentate gyrus.